Prostaglandin E2 (abbreviated as PGE2) has been known as a metabolite in the arachidonate cascade. It has also been known that PGE2 possesses a cyto-protective activity, a uterine contractive activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, a hypotensive effect, a diuretic activity and so on.
In a recent study, it was found that a PGE2 receptor is divided into some subtypes which possess different physical roles from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 respectively (Negishi M. et al., J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
PGE2 possesses a variety of physiological activities, so the undesired action other than the aimed one is shown as side effect. The research for the role of each receptor subtype and the investigation of the compound which only shows the effect on the specific subtype have been carried out to overcome such a problem.
Among these subtypes, it has been known that EP1 subtype relates to induction pain, pyrexia (induction fever) and diuresis (ref Br. J. Pharmacol., 112, 735-740 (1994); European J. Pharmacol., 152 273-279 (1988); Gen Pharmacol., September 1992, 23(5) 805-809). Therefore, compounds which antagonize this receptor are considered to be useful as analgesics, as antipyretic agents and as agents for treating pollakiuria (frequent urination).
It has also been known that EP1 antagonists possess a suppressive effect on aberrantcryptfoci and formation of intestinal polyps, and that they indicate an effective anti-tumor activity (ref. WO00/69465).
After drugs are absorbed in the body, they mainly migrate into the bloodstream. Then they are transported in the blood and are delivered to target organs. Finally they exert their potency. However, some drugs do not exert their potency because they combine with some proteins, which is contained in blood as nutritive substances. While some compounds are effective in in vitro experiment, it may often turn out that they are not effective in in vivo experiment. And it has been well known that there is not a specific structure-activity relationship on binding between drugs and proteins, and that it is very difficult to find out the ordinality.
The present inventors found a useful compound which is an EP1 antagonist, and filed a patent application. In the specification of WO98/27053 (EP947500), it is disclosed that a sulfonamide compound of formula (A)
wherein the group
are each independently C5-15 carbocyclic ring etc.; Z1A is —COR1 etc.; Z2A is hydrogen etc.; R1A is hydroxy etc.; Z3A is single bond etc.; Z4A is SO2 etc.; Z5A is 5 to 7 membered heterocyclic ring containing one or two oxygen, sulfur or nitrogen atom(s), which may be substituted with 1 to 5 R5A etc.; R5A (if two or more R5A, each independently) is hydrogen, C1-6 alkyl etc.; R2A is Z7A-C1-4 alkylene etc.; Z7A is oxygen etc.; R3A is trifluoromethyl etc.; R4A is C1-8 alkyl etc.; nA and tA are each independently 1 to 4 (as excerpt),binds to a PGE2 receptor, especially the EP1 receptor, to show an agonistic or an antagonistic activity. The specification disclosed that the compound having the antagonistic activity is useful for the prevention of abortion, as an analgesic, as an antidiarrhoic, as a hypnagogic agent and for treating pollakiuria (frequent urination), while the one having an agonistic activity is useful for abortion, as an abstergent, as an antiulcer agent, as an antigastritis agent, as an antihypertensive agent, as a diuretic agent.
In this patent application, for example, the following compounds are disclosed specifically.